Kengo Kanetaka

Background: Fibrosis is a prominent component of the gastric cancer microenvironment; however, its intratumoral patterns remain poorly characterized. In this study, we employed multidimensional phenotypic profiling to provide a comprehensive characterization of tumour‐associated fibrosis and evaluate its association with histological subtypes and clinical outcomes in gastric carcinomas with poorly differentiated histology. Methods: Of the 392 patients with gastric cancer who underwent gastrectomy at our centre during the study period, 30 patients with T3 tumours were selected for analysis, comprising signet‐ring cell carcinoma (SRC), poorly differentiated adenocarcinoma, non‐solid type (por2), as well as poorly differentiated adenocarcinoma, solid type (por1). Fibrosis phenotypes were quantified using FibroNest™, a digital pathology platform enabling single‐fibre assessment of collagen quantity, morphology and structural organization. Key quantitative fibrosis traits (qFTs) were integrated into a phenotypic fibrosis composite score for gastric cancer (Ph‐FC‐GC). Results: Ph‐FCS‐GC differentiated the overall fibrosis patterns of por1 from those of SRC and por2, although no clear differences in individual fibrosis features were observed between por2 and SRC. Importantly, Ph‐FCS‐GC also effectively discriminated between tumours with and without lymph node metastasis. qFT analysis revealed previously uncharacterized heterogeneity in collagen morphometrics, such as fibre length and branching, in non‐metastatic tumours, whereas metastatic tumours showed more uniform architectures. Tumours with 3‐year recurrence exhibited lower porous area ratios and more spatially ordered collagen networks, indicating denser, more organized fibrosis than non‐recurrent tumours. Conclusions: Collagen morphology and architecture differ according to histological subtype and may provide prognostic insights into lymph node metastasis and recurrence in gastric cancer.

Cell transplantation using cell sheet technology is a promising regenerative approach that enables the delivery of a large number of viable cells while preserving cell–cell interactions and extracellular matrix. However, the clinical application of autologous cell sheets is limited by donor-site invasiveness, prolonged preparation time, and high manufacturing costs. Allogeneic cell sheets may overcome these limitations, but their therapeutic effects and immunological profiles require further clarification. In this study, we investigated the tissue-repair effects and immune responses associated with allogeneic skeletal muscle-derived cell (SMDC) sheet transplantation. In vitro analyses showed that human SMDCs suppressed activated T-cell proliferation in a cell number-dependent manner, lacked co-stimulatory molecules, and expressed immune checkpoint ligands, suggesting a potentially low-immunogenic and immunomodulatory phenotype. For in vivo evaluation, L8-derived syngeneic comparator sheets and allogeneic SMDC sheets derived from different rat strains were transplanted onto the serosal surface in a rat gastric ulcer model. SMDC sheet transplantation promoted early ulcer repair without increasing systemic inflammatory responses, as assessed by serum C-reactive protein levels. Histological analyses revealed limited macrophage and T-cell infiltration at the transplantation sites, although the extent of local immune responses varied depending on donor–recipient strain combinations. Transcriptomic analysis of ulcer tissues showed that the L8-derived syngeneic comparator and selected allogeneic groups shared downregulation of inflammation-related pathways, whereas another allogeneic donor strain induced a distinct transcriptional profile. These findings suggest that allogeneic SMDC sheets can promote early tissue repair without inducing overt systemic inflammatory activation. However, donor–recipient strain compatibility may influence local immunological and transcriptional responses after transplantation. The observed effects are consistent with early paracrine and immunomodulatory mechanisms, although direct cell tracking and more detailed immunological analyses are required. Allogeneic SMDC sheets may represent a potential ready-to-use strategy for gastrointestinal tissue repair, provided that appropriate donor selection and further preclinical validation are performed.

Association between surgical timing and postoperative outcome in patients with residual esophageal cancer after neoadjuvant chemoradiotherapy

Background Heat-not-burn cigarettes (HNBCs) are marketed as reduced-risk combustible cigarette alternatives. However, their impact on surgical outcomes after invasive procedures, including esophagectomy, remains unclear. To evaluate the association between preoperative HNBC use and short-term outcomes after oncological esophagectomy. Methods This retrospective cohort study utilized Japanese National Clinical Database data from patients who underwent esophagectomy for thoracic esophageal cancer between January 2019 and December 2021. The exposure was self-reported HNBC use within 1 year before surgery. The primary outcome was operative mortality. Secondary outcomes included life-threatening complications (Clavien–Dindo classification ≥ IV), anastomotic leakage, postoperative pneumonia, surgical site infection, and prolonged mechanical ventilation (≥ 48 h). Associations between HNBC use and outcomes were assessed using multilevel logistic regression models, adjusting for patient demographics, comorbidities, combustible cigarette smoking history, alcohol use, and tumor characteristics. Results Of 17,797 patients, 589 (3.3%) reported preoperative HNBC use. HNBC users were younger and male, with higher rates of concurrent combustible cigarette use (85.2% vs. 33.2%), intense smoking history (Brinkman index ≥ 600:67.2% vs. 47.9%), and habitual alcohol consumption (80.5% vs. 66.6%) than non-users. After adjusting for confounders, HNBC use was associated with nonsignificant trends toward increased operative mortality [adjusted odds ratio (aOR): 1.82, 95% confidence interval (CI): 0.95–3.48; P = 0.07] and life-threatening complications (aOR: 1.56, 95% CI: 0.98–2.48; P = 0.06). No other secondary outcomes were significantly associated with HNBC use. Conclusions The observed trends, although nonsignificant, suggest that preoperative HNBC use may be associated with increased risks of operative mortality and life-threatening complications, warranting further investigation.

Purpose : Cost discussions are essential but seldom conducted in routine oncology care. Here, we evaluated whether using a drug cost calculation tool improves patients’ understanding of drug costs and their perception of the importance of drug costs in making treatment decisions for advanced breast cancer (ABC). Methods : This multicenter, open-label, randomized phase 2 trial was conducted at four hospitals in Japan. Eligible patients with ABC were randomized on a one-to-one basis to the drug cost calculator or usual-explanation group. Physicians in the calculator group used the calculator to explain out-of-pocket drug costs during treatment consultations. The co-primary endpoints were patients’ scores on two five-point Likert-scale questions assessing (1) understanding of drug costs and (2) perception of their importance in treatment decisions. Results : Ninety-eight patients were enrolled, of whom 69 were randomized between September 2019 and November 2023. The median score for “understanding of drug costs” was 4 (IQR, 3–4) and 3 (IQR, 2–4) points in the calculator and usual-explanation groups, respectively ( P = 0.04). For “importance of drug costs,” the median scores were 4 (IQR, 4–5) and 4 (IQR, 3–4) points in the calculator and usual-explanation groups, respectively. The scores for “discussion of financial burden” tended to be higher in the calculator group. Consultation times were comparable between the groups. Conclusion : Using the drug cost calculator tended to improve patients’ understanding of drug costs and facilitated cost communication without prolonging consultation time. Trial registration : University Hospital Medical Information Network Clinical Trials Registry (No. UMIN000039904; March 23, 2020).

Background: The detection rate of superficial non-ampullary duodenal epithelial tumors (SNADETs) has recently been increasing. Large tumors may contain malignant lesions and early therapeutic intervention is recommended. Endoscopic mucosal dissection (ESD) is considered a feasible treatment modality, however, the anatomical and physiological characteristics of the duodenum create a risk of postoperative perforation after ESD. Methods: To explore whether myoblast sheet transplantation could prevent delayed perforation after ESD, a first-in-human (FIH) clinical trial of laparoscopic autologous myoblast sheet transplantation after duodenal ESD was launched. Autologous myoblast sheets fabricated from muscle tissue obtained seven weeks before ESD were transplanted laparoscopically onto the serous side of the ESD. The primary endpoints were the onset of peritonitis due to delayed perforation within three days after surgery and all adverse events during the follow-up period. Results: Three patients with SNADETs ≥ 20 mm in size underwent transplantation of a myoblast sheet onto the serous side of the duodenum after ESD. In case 1, The patient’s postoperative course was uneventful. Endoscopy and abdominal computed tomography revealed no signs of delayed perforation. Despite incomplete mucosal closure in case 2, and multiple micro perforations during ESD in case 3, cell sheet transplantation could prevent the postoperative massive perforation after ESD, and endoscopy on day 49 after transplantation revealed no stenosis. Conclusions: This clinical trial showed the safety, efficacy, and procedural operability of this novel regenerative medicine approach involving transplanting an autologous myoblast sheet laparoscopically onto the serosa after ESD in cases with a high risk of delayed perforation. This result indicates the potential application of cell sheet medicine in treating various abdominal organs and conditions with minimal invasiveness in the future. Trial registration: jRCT, jRCT2073210094. Registered November 8 2021, https://jrct.niph.go.jp/latest-detail/jRCT2073210094.

Liver metastasis in gastric cancer is incurable. Alpha-fetoprotein-producing gastric cancer has a poor prognosis and is prone to liver metastasis. We investigated the association between preoperative serum alpha-fetoprotein levels, liver metastasis, and expression of primitive enterocyte phenotype markers. We reviewed the medical records of 401 patients with gastric cancer who underwent curative surgical resection and immunohistochemically evaluated the primitive phenotype markers. The preoperative serum alpha-fetoprotein levels were elevated and normal in 8 and 393 patients, respectively. Liver metastasis was more frequent in patients with higher preoperative alpha-fetoprotein levels. The 5-year postoperative recurrence-free survival and overall survival rates were significantly worse in patients with higher preoperative serum alpha-fetoprotein levels. Although alpha-fetoprotein and Glypican3 and Spalt-like transcription factor 4 tended to be stained with high preoperative serum alpha-fetoprotein levels, these markers were also positive in some patients with normal alpha-fetoprotein levels. In summary, patients with gastric cancer and high preoperative serum alpha-fetoprotein levels have a poor prognosis and high incidence of liver metastasis. Alpha-fetoprotein can help detect liver metastasis relating to the primitive enterocyte phenotype.

We report a case of pathologic complete response after successful treatment for advanced hepatocellular carcinoma (HCC) complicated with portal venous tumor thrombus with atezolizumab and bevacizumab followed by radical resection. The patient was a male in his 60s. During follow-up for chronic hepatitis B, abdominal ultrasonography revealed a huge tumor located in the right lobe of the liver with the portal vein thrombosed by the tumor. The tumor thrombus extended to the proximal side of the left branch of the portal vein. The patient’s tumor marker levels were elevated (alpha-phetoprotein, 14,696 ng/mL; PIVKA-II, 2,141 mAU/mL). Liver biopsy revealed poorly differentiated HCC. The lesion was categorized as advanced stage according to the BCLC staging system. As systemic therapy, atezolizumab plus bevacizumab was administered. Imaging showed marked shrinkage of the tumor and portal venous thrombus with a remarkable decrease of tumor marker levels after 2 courses of chemotherapy. After 3 additional courses of chemotherapy, radical resection was considered possible. The patient underwent right hemihepatectomy and portal venous thrombectomy. A pathological examination revealed a complete response. In conclusion, we experienced a case in which advanced HCC was curatively treated with atezolizumab plus bevacizumab, which was administered as systemic therapy with a view to conversion surgery.

Management of Spontaneous Portosystemic Shunts in 231 Patients Who Underwent Living Donor Liver Transplantation: A Retrospective Study from a Single Center in Nagasaki, Japan - Article abstract #936371